In eukaryotes, phospholipids that constitute plasma membrane are distributed asymmetrically in outer and inner leaflets. Phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn) are present in the inner leaflets, while phosphatidylcholine (PtdCho) and sphingomyelin (SM) are mainly in the outer leaflet. The asymmetrical distribution of PtdSer and PtdEtn on the plasma membrane is maintained in an ATP-dependent manner by aminophospholipid translocase. The asymmetrical distribution of phospholipids is disrupted in various biological processes, and PtdSer exposed on the cell surface acts as a signaling molecule. For example, PtdSer exposed on apoptotic cells is an “eat me” signal for macrophages. On the activated platelets, PtdSer exposed on the cell surface activates blood coagulation factors and triggers the blood clotting.
PtdSer exposure to the cell surface is mediated by a phospholipid scramblase. However, the identity of the scramblase(s) has been unclear. Recently, TMEM16F has been identified as a Ca2+-dependent phospholipid scramblase involved in the PtdSer exposure in activated platelets. However, TMEM16F-deficient cells exposed PtdSer in response to apoptotic stimuli as wild-type cells did, suggesting that TMEM16F has little involvement in apoptotic PtdSer exposure.